Ethnically Diverse iPSC-Cardiomyocyte Panel for Pharmacogenomics and Drug Safety Testing

项目摘要 药物毒性是药物开发过程中早期和晚期药物消耗的主要原因。的 FDA现在要求所有新药在进入临床试验之前进行心脏毒性测试。但 需要成为一个安全筛查平台，可以快速检测心脏毒性，具有成本效益，甚至在 在药物开发管道上投入了太多的时间和资源。这是进一步复杂化的基因组 人群中的易感性以及他们对药物的反应。一种可以融合性的影响的工具， 种族和遗传背景可以提供关于药物安全性和有效性的准确数据， 患者人群，以确定应答者与非应答者。在这次SBIR拨款中，我们建议减轻这一点， 通过使用人类诱导多能干细胞提供药物基因组学和精确医学平台 细胞衍生的心肌细胞（iPSC-CM）。我们的产品是一个包含100个独特和种族多样的iPSC的试剂盒 性别平等的路线。我们的目标是开发和验证这种工具作为替代体外模型， 预测药物诱发心律失常高危人群的药物毒性。这项研究将使用“细胞 village”平台同时共培养10个不同的患者特异性iPSC系。我们将扩大规模， 来自100个不同供体的多路复用数据以鉴定细胞类型特异性表达数量性状基因座（eQTL） 使用单细胞RNA测序（scRNA-seq）和全基因组测序（WGS）。作为原理证明， 我们还将评估个体间和个体内对化疗剂的反应的变异性 阿霉素最后，Greenstone Biosciences，Inc是一家位于斯坦福大学研究中心的生物技术公司。 公园Greenstone利用临床基因组学、计算生物学和患者特异性iPSC的最新进展 来理解药物基因组学和加速药物发现。

PROJECT SUMMARY Cardiotoxicity is a leading cause of early and late-stage drug attrition during pharmaceutical development. The FDA now mandates that all new drugs be tested for cardiotoxicity before entering clinical trials. However, there needs to be a safety screening platform that can swiftly detect cardiotoxicity cost-effectively, even before investing too much time and resource in a drug development pipeline. This is further complicated by genomic susceptibility in the population and how they respond to drugs. A tool that can incorporate the influences of sex, ethnicity, and genetic background can provide accurate data on the safety and efficacy of drugs and stratify patient populations to identify responders versus non-responders. In this SBIR grant, we propose to mitigate this issue by providing pharmacogenomics and precision medicine platforms using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our product is a kit comprising 100 unique and ethnically diverse iPSC lines with equal sex representation. We aim to develop and validate this tool as a surrogate in vitro model for predicting drug toxicity in patient groups at high risk for drug-induced arrhythmia. The study will use the “cell village” platform to co-culture 10 different patient-specific iPSC lines simultaneously. We will scale this up by multiplexing data from 100 different donors to identify cell-type-specific expression quantitative trait loci (eQTL) using single-cell RNA sequencing (scRNA-seq) and whole genome sequencing (WGS). As a proof-of-principle, we will also assess inter-individual and intra-individual variability in responses to the chemotherapeutic agent doxorubicin. Finally, Greenstone Biosciences, Inc is a biotechnology company located at the Stanford Research Park. Greenstone uses latest advances in clinical genomics, computational biology, and patient-specific iPSCs to understand pharmacogenomics and to accelerate drug discovery.